Abstract:Summary
Mutations in the lipid transport protein ABCA12 cause the life-threatening skin condition harlequin ichthyosis (HI), which is characterized by the loss of skin barrier function, inflammation, and dehydration. Inflammatory responses in HI increase disease severity by impairing keratinocyte differentiation, suggesting amelioration of this phenotype as a possible therapy for the condition. Existing treatments for HI are based around the use of retinoids, but their value in treating patients dur… Show more
“…Since HI is the most severe skin barrier disease, we reasoned that targeted deletion of Abca12, the causative gene mutated in HI 9,10 , would provide us a tool to disrupt lamellar granules and interrogate barrier function in different epithelial sub-compartments. We therefore first generated mice harboring a null allele of Abca12 that is constitutively disrupted by a LacZ insertion between exons 3 and 4, similar to previously described 33 (Figure S2A-B). Newborn homozygous mutant pups (Abca12-KO) recapitulated HI features, including taut, shiny skin; thickened and compacted stratum corneum; and death from rapid dehydration [34][35][36] (Figure 2A).…”
Section: Validating a Genetic Tool To Disrupt Barrier Functionmentioning
Our skin provides a protective barrier that shields us from our environment. Barrier function is typically associated with interfollicular epidermis; however, whether hair follicles influence this process remains unclear. Here, we utilize a potent genetic tool to probe barrier function by conditionally ablating a quintessential epidermal barrier gene, Abca12, which is mutated in the most severe skin barrier disease, harlequin ichthyosis. With this tool, we deduced 4 ways by which hair follicles modulate skin barrier function. First, the upper hair follicle (uHF) forms a functioning barrier. Second, barrier disruption in the uHF elicits non-cell autonomous responses in the epidermis. Third, deleting Abca12 in the uHF impairs desquamation and blocks sebum release. Finally, barrier perturbation causes uHF cells to move into the epidermis. Neutralizing Il17a, whose expression is enriched in the uHF, partially alleviated some disease phenotypes. Altogether, our findings implicate hair follicles as multi-faceted regulators of skin barrier function.
“…Since HI is the most severe skin barrier disease, we reasoned that targeted deletion of Abca12, the causative gene mutated in HI 9,10 , would provide us a tool to disrupt lamellar granules and interrogate barrier function in different epithelial sub-compartments. We therefore first generated mice harboring a null allele of Abca12 that is constitutively disrupted by a LacZ insertion between exons 3 and 4, similar to previously described 33 (Figure S2A-B). Newborn homozygous mutant pups (Abca12-KO) recapitulated HI features, including taut, shiny skin; thickened and compacted stratum corneum; and death from rapid dehydration [34][35][36] (Figure 2A).…”
Section: Validating a Genetic Tool To Disrupt Barrier Functionmentioning
Our skin provides a protective barrier that shields us from our environment. Barrier function is typically associated with interfollicular epidermis; however, whether hair follicles influence this process remains unclear. Here, we utilize a potent genetic tool to probe barrier function by conditionally ablating a quintessential epidermal barrier gene, Abca12, which is mutated in the most severe skin barrier disease, harlequin ichthyosis. With this tool, we deduced 4 ways by which hair follicles modulate skin barrier function. First, the upper hair follicle (uHF) forms a functioning barrier. Second, barrier disruption in the uHF elicits non-cell autonomous responses in the epidermis. Third, deleting Abca12 in the uHF impairs desquamation and blocks sebum release. Finally, barrier perturbation causes uHF cells to move into the epidermis. Neutralizing Il17a, whose expression is enriched in the uHF, partially alleviated some disease phenotypes. Altogether, our findings implicate hair follicles as multi-faceted regulators of skin barrier function.
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